U.S. patent application number 10/113205 was filed with the patent office on 2004-03-18 for substituted 1,2,4-trioxanes useful as antimalarial agents and a process for the preparation thereof.
Invention is credited to Puri, Sunil Kumar, Singh, Chandan, Tiwari, Pallvi.
Application Number | 20040053991 10/113205 |
Document ID | / |
Family ID | 31990070 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053991 |
Kind Code |
A1 |
Singh, Chandan ; et
al. |
March 18, 2004 |
Substituted 1,2,4-trioxanes useful as antimalarial agents and a
process for the preparation thereof
Abstract
In the present invention relates to a novel series of
antimalarial 1,2,4-trioxanes analogues of general formula 7, 1
wherein R represents cycloalkyl groups selected from the groups
consisting of cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
or aryl groups selected from phenyl, 4-bromophenyl and
4-chlorophenyl, R.sub.1 and R.sub.2 represent hydrogen, alkyl group
selected from methyl, ethyl, propyl and decyl, aryl selected from
phenyl or parts of a cyclic systems such as cyclopentane,
cyclohexane, substituted cyclohexane, cycloheptane
bicyclo(2.2.1)heptane, adamantane and its preparation thereof;
several of these novel compounds show promising antimalarial
activity against multidrug resistant malaria in mice.
Inventors: |
Singh, Chandan; (Uttar
Pradesh, IN) ; Tiwari, Pallvi; (Uttar Pradesh,
IN) ; Puri, Sunil Kumar; (Uttar Pradesh, IN) |
Correspondence
Address: |
MORGAN & FINNEGAN, L.L.P.
345 Park Avenue
New York
NY
10154-0053
US
|
Family ID: |
31990070 |
Appl. No.: |
10/113205 |
Filed: |
March 28, 2002 |
Current U.S.
Class: |
514/452 ;
549/352 |
Current CPC
Class: |
Y02A 50/30 20180101;
C07D 323/04 20130101 |
Class at
Publication: |
514/452 ;
549/352 |
International
Class: |
A61K 031/335; C07D
323/02 |
Claims
1. Novel substituted 1,2,4-trioxanes of formula 7 having
antimalarial activity, wherein R represents cycloalkyl groups
selected from the groups consisting of cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl or aryl groups selected from phenyl,
4-bromophenyl and 4-chlorophenyl, R.sub.1 and R.sub.2 represent
hydrogen, alkyl group selected from methyl, ethyl, propyl and
decyl, aryl selected from phenyl, or part of a cyclic system such
as cyclopentane, cyclohexane, substituted cyclohexane,
cycloheptane, cyclo(2.2.1)heptane, adamantane. 6
2. Novel 1,2,4-trioxanes as claimed in claim 1 wherein the said
compounds having the structural formula 7aa-ae as shown below: 77aa
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH7ab
R.sub.1=R.sub.2=--CH.sub.- 2CH.sub.2CH(Ph)CH.sub.2CH.sub.2--7ac
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.- sub.2CH.sub.2CH.sub.2--7ad
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.su-
b.2CH.sub.2CH.sub.2--7ae
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub-
.3).sub.2CH.sub.2CH.sub.3]-CH.sub.2CH.sub.2--
3. Novel 1,2,4-trioxanes as claimed in claim 1-2 wherein the said
compounds having the structural formula 7ba-bi as shown below: 87ba
R.sub.1=R.sub.2=CH.sub.3 7bb R.sub.1=CH.sub.3;
R.sub.2=--CH.sub.2(--CH.su- b.2).sub.8--CH.sub.3 7bc R.sub.1=H;
R.sub.2=phenyl 7bd
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--7be
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2--CH(Ph)-CH.sub.2CH.sub.2--7bf
R.sub.1=CH.sub.3; R.sub.2=, CH.sub.2CH.sub.3 7bg R.sub.1=CH.sub.3;
R.sub.2=--CH.sub.2CH.sub.2CH.sub.3 7bh
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2- CH.sub.2CH.sub.2--7bi
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub.3)-
.sub.2CH.sub.2CH.sub.3]--CH.sub.2CH.sub.2--
4. Novel 1,2,4-trioxanes as claimed in claim 1-3 wherein the said
compounds having the structural formula 7ca-cd as shown below: 97ca
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--7cb
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub.2CH.sub.2CH.sub.-
3]--CH.sub.2CH.sub.2--7cc
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH.sub.2--- CH.sub.2--7cd
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2--CH(Ph)-CH.sub.2CH.sub.2-- -
5. Novel 1,2,4-trioxanes as claimed in claim 1-4 wherein the said
compounds having the structural formula 7da-df as shown below:
107da R.sub.1, =CH.sub.3; R.sub.2=--CH.sub.2CH.sub.3 7 db
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--7dc
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.su-
b.2--7dd
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH(Ph)CH.sub.2CH.sub.2--7de
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--7df
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub.2CH.sub.2CH.sub.-
3]--CH.sub.2CH.sub.2--
6. Novel 1,2,4-trioxanes as claimed in claim 1-5 wherein the said
compounds having the structural formula 7ea-eh as shown below:
117ea R.sub.1=H; R.sub.2=phenyl 7eb
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2C- H.sub.2--7ec
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--7- ed
R.sub.1=CH.sub.3;
R.sub.2=--CH.sub.2(--CH.sub.2).sub.8--CH.sub.2--7ee
R.sub.1=R.sub.2=CH.sub.3 7ef
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH(Ph)CH.s- ub.2CH.sub.2--7eg
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub-
.2CH.sub.2CH.sub.3]--CH.sub.2CH.sub.2--7eh
R.sub.1=R.sub.2=--CH.sub.2CH.su-
b.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--
7. Novel 1,2,4-trioxanes as claimed in claim 1-6 wherein the said
compounds having the structural formula 7fa-ff as shown below:
127fa R.sub.1, =R.sub.2=CH.sub.3 7fb R.sub.1=CH.sub.3;
R.sub.2=CH.sub.2CH.sub.3 7fc
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--7fd
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub.2CH.sub.2CH.sub.-
3]--CH.sub.2CH.sub.2--7fe
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub- .2--7ff
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2--CH(Ph)-CH.sub.2CH.sub.2--
8. Novel trioxanes as claimed in claim 1-7 wherein the said
compounds having the structural formulae 7ga-ge as shown below:
137ga R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--7gb
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--7gc
R.sub.1=R.sub.2=--CH.sub.2CH.sub.2--CH(Ph)-CH.sub.2CH.sub.2--7gd
R.sub.1=R.sub.2=--CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub.2CH.sub.2CH.sub.-
3]--CH.sub.2CH.sub.2--7ge R.sub.1=CH.sub.3;
R.sub.2=--CH.sub.2CH.sub.3
9. Novel trioxanes as claimed in claim 1-7 wherein the said
compounds having the structural formulae 8a-g as shown below: 148a
R=cyclopentyl 8b R=cyclohexyl 8c R=cycloheptyl 8d R=cyclooctyl 8e
R=Phenyl 8f R=4-Br-Phenyl 8g R=4-Cl-Phenyl
10. Novel trioxanes as claimed in claim 1-9 wherein the said
compounds having the structural formulae 9a-g as shown below: 159a
R=cyclopentyl 9b R=cyclohexyl 9c R=cycloheptyl 9d R=cyclooctyl 9e
R=Phenyl 9f R=4-Br-Phenyl 9g R=4-Cl-Phenyl
11. A process for the preparation of substituted 1,2,4-trioxane of
general formula (7), the said process comprising steps of: (a)
reacting aryl alkyl ketone of formula (1) with alkyl halo acetate
of formula (2) in presence of zinc, catalytic amount of iodine in
an aprotic organic solvent at a temperature ranging between
20.degree.-120.degree. C. for a period of 2-8 hours, (b) acidifying
the reaction mixture of step (a) using aqueous 10% aqueous
hydrochloric acid, separating the organic layer, (c) washing the
organic layer of step (b) with water, drying over anhydrous sodium
sulphate, filtering, evaporating to obtain a residue, (d) purifying
the residue of step (c) over silica gel column, eluting with
mixture of hexane:ethylacetate to obtain .beta.-hydroxyester of
general formula (2), (e) dehydrating the .beta.-hydroxyester of
general formula (2) of step (d) with a dehydrating agent in an
organic aprotic solvent at a temperature range of
20.degree.-120.degree. C. for a period of 2-5 hours, (f) diluting
the reaction mixture of step (e) with saturated sodium bicarbonate
solution, separating organic layer, (g) washing the organic layer
of step (f) with water, drying the organic layer over anhydrous
sodium sulphate, filtering and evaporating to obtain a residue, (h)
purifying the residue of step (g) over silica gel columns to obtain
the .alpha.,.beta.-unsaturated ester of general formula (3), (i)
reducing the .alpha.,.beta.-unsaturated ester of general formula
(3) of step (h) with metal hydride in an anhydrous ethereal solvent
at a temperature range of 0.degree.-80.degree. C. for a period of
2-10 hours, (j) quenching the reaction mixture of step (i), by
adding water, further adding aqueous alkali hydroxide solution,
separating the organic layer by filtering, washing the residue with
the organic solvent to obtain combined organic solvent soluble
fraction, (k) evaporating the combined organic solvent soluble
fraction of step (j) to dryness to obtain a product residue, (l)
purifying the residue of step (k) over silica gel column to obtain
the allylic alcohol of general formula (4), (m) dissolving the
allylic alcohol of general formula (4) of step (l) in an organic
solvent to obtain a solution, (n) irradiating the solution of step
(m) with a 250 watt tungsten halogen lamp, in presence of a
sensitizer at a temperature range of -50 to -10.degree. C. for a
period 3-10 hours, (o) optionally adding water to the reaction
mixture of step (n) separating organic layer, evaporating and
crystallising the residue to obtain the required
.beta.-hydroxy-hydroperoxide compound of general formula (5), (p)
reacting the .beta.-hydroxy hydroperoxide compound of general
formula (5) with an aldehyde or ketone of formula (6) in an organic
solvent in presence of an acid catalyst at room temperature for a
period of 16-24 hours, (q) adding water to the reaction mixture of
step (p), separating organic layer, drying and evaporating the
organic layer to obtain a residue, (r) purifying by crystallising
the residue of (q) to obtain the required substituted
1,2,4-trioxane analogues of general formula (7), and (s) analogues
of general formula (7) can also be obtained by performing steps (q)
to (r) in the reaction mixture of step (n).
12. A process as claimed in claim 11 wherein in step (a) alkyl
group of the aryl alkyl ketone used is selected from a group
consisting of cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl.
13. A process as claimed in claim 11 wherein in step (a) the aryl
group of the aryl alkyl ketone used is selected from a group
consisting of phenyl, 4-bromophenyl, or 4-chlorophenyl.
14. A process as claimed in claim 11 wherein in step (a) the alkyl
halo acetate is selected from a group consisting of ethyl
bromoacetate or ethyl chloroacetate.
15. A process as claimed in claim 11, wherein in step (a), the
aprotic solvent is selected from a group consisting of diethyl
ether, benzene, toluene or tetrahydrofuran.
16. A process as claimed in claim 11, wherein in step (e) the
dehydrating agent used is selected from a group consisting of
iodine, phosphorus pentoxide or p-toluene sulphonic acid.
17. A process as claimed in claim 11 wherein kin step (e) the
organic solvent used is selected from a group consisting of
dichloromethane, chloroform, benzene or toluene.
18. A process as claimed in claim 11 wherein in step (i) the metal
hydride used is lithium aluminium hydride.
19. A process as claimed in claim 11 wherein in step (i) the
anhydrous etheral solvent used is selected from a group consisting
of diethylether or tetrahydrofuran.
20. A process as claimed in claim 11 wherein in step (m) the
organic solvent used is selected from a group consisting of
dichloromethane, benzene, acetonitrile or methanol.
21. A process as claimed in claim 11, wherein in step (n) the
sensitizer used is a dye selected from a group consisting of
methylene blue, Rose Bengal or tetraphenyl porphine.
22. A process as claimed in claim 11 wherein in step (p) the
organic solvent used is selected from a group consisting of
dichloromethane, chloroform, acetonitrile or benzene.
23. A process as claimed in claim 11 wherein in step (p) the acid
catalyst used is selected from a group consisting of hydrochloric
acid, sulphuric acid, p-toluene sulphoric acid or acidic resin.
24. A process as claimed in claim 11 wherein in step (p) the
aldehyde or ketone used is selected from a group consisting of
acetone, ethylmethyl ketone, methyl propyl ketone, decyl ketone,
cyclopentanone, cyclohexanone, cycloheptanone, 4-phenyl
cyclohexanone, 4-t-anyl cyclohexanone, cyclokeptanone, norcamphor,
2-alamantone, substituted or unsubstituted phenyl derivative.
25. Use of 1,2,4-trioxane analogues as claimed in claims 1 to 10
for treating malaria in a subject, comprising administering
pharmaceutically effective dosage of said analogues optionally with
additive to the said subject in need thereof.
26. Use as claimed in claim 25 wherein 1,2,4-trioxane analogues are
used singly or in combination with pharmaceutically acceptable
carrier.
27. Use as claimed in claim 25 wherein the analogues of
1,2,4-trioxane are administered intramuscularly or orally.
28. Use as claimed in claim 25 wherein the subject is swiss mice.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel series of
antimalarial 1,2,4-trioxanes analogues of general formula 7, 2
[0002] wherein R represents cycloalkyl groups selected from the
groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and
4-chlorophenyl, R.sub.1 and R.sub.2 represent hydrogen, alkyl group
selected from methyl, ethyl, propyl and decyl, aryl selected from
phenyl or parts of a cyclic systems such as cyclopentane,
cyclohexane, substituted cyclohexane, cycloheptane
bicyclo(2.2.1)heptane, adamantane and its preparation thereof;
several of these novel compounds show promising antimalarial
activity against multidrug resistant malaria in mice.
BACKGROUND OF INVENTION
[0003] Malaria, endemic in many parts of the tropical countries,
with approximately 300-500 million episodes of clinical infection
and nearly 2 million deaths per year worldwide, is a serious health
problem. The rapid emergence of resistance by Plasmodium falciparum
to the existing therapies, e.g. chloroquine, mefloquine etc, has
added new dimensions to this problem. Against this background
discovery of artemisinin 1, a sesquiterpene lactone endoperoxide,
isolated from the Chinese traditional herbal remedy against
malaria, Artemisia annua, has been a welcome development in the
chemotherapy of malaria. Some of the semisynthetic derivatives of
artemisinin e.g. artemether 2, arteether 3, and artesunic acid 4
are more active than artemisinin and are currently being used
clinically. These drugs are effective against both chloroquine
sensitive and chloroquine resistant strains of Plasmodium
falciparum [For reviews on artemisinin and its derivatives, see:
(a) Klayman, D. L. Science, 1985, 228, 1049; (b) Luo, X. D.; Shen,
C. C. Med. Res. Rev., 1987, 7, 29; (c) Zaman, S. S.; Sharma, R. P.
Heterocycles, 1991,32,1593; (d) Butler, A. R.; Wu, Y. Lin. Chem.
Soc. Rev., 1993, 21,85; (e) Meshnick, S. R.; Taylor, T. E.;
Kamchonwongpaisan, S. Microbiol. Rev., 1996, 60,301; (f)
Bhattacharya, A. K.; Sharma, R. P. Heterocycles, 1999, 51, 1681;
(g) Haynes, R. K.; Vonwiller, S.C. Acc. Chem. Res., 1997, 73].
3
[0004] The limited availability of artemisinin from natural sources
and the realization that 1,2,4-trioxane is the pharmacophore for
the antimalarial activity of artemisinin and its analogues, has
inspired major efforts towards the preparation and bioevaluation of
structurally simple synthetic 1,2,4-trioxanes. As a result of these
efforts, a number of methodologies have been developed by various
workers for the preparation of 1,2,4-trioxanes (prototypes of these
trioxanes are given in FIG. 1). Several of these synthetic
trioxanes have shown promising antimalarial activities both in
vitro and in vivo [Cumming, J. M.; Ploypradith, P.; Posner, G. H.
Adv Pharmacol, 1999, 37,253]. 4
[0005] Singh et al. have prepared 1,2,4-trioxanes by the
regiospecific photooxygenation of allylic alcohols to furnish
-hydroxyhydroperoxide, which on condensation with aldehyde or
ketone in the presence of an acid catalyst furnish 1,2,4-trioxane
[(a) Singh, C. Tetrahedron Lett. 1990,31,6901;(b) Singh, C.; Misra,
D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett., 1992, 2, 497;
Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem.
Lett., 1995,17, 1913]. As an extension of this work we have
prepared a new series of novel 1,2,4-trioxanes which have been
found to be highly active against multi-drug resistant P. yoelii in
mice and which are the subject matter of this patent.
[0006] This invention relates to novel substituted 1,2,4-trioxanes
useful as antimalarial agents.
[0007] This invention also relates to a process for the preparation
of novel substituted 1,2,4-trioxanes.
[0008] This invention particularly relates to a process for the
preparation of 6-[(cycloalkylphenyl/Substituted biphenyl)
vinyl]-1,2,4-trioxanes, a new series of antimalarial agents. More
particularly the present invention provides a process for the
preparation of 1,2,4-trioxanes of general formula 7 wherein R
represents cycloalkyl groups selected from the groups consisting of
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or aryl groups
selected from phenyl, 4-bromophenyl and 4-chlorophenyl, R.sub.1 and
R.sub.2 represent hydrogen, alkyl group selected from methyl,
ethyl, propyl and decyl, aryl selected from phenyl, or part of a
cyclic system such as cyclopentane, cyclohexane, substituted
cyclohexane, cycloheptane, cyclo(2.2.1)heptane, adamantane. These
trioxanes are new compounds and are useful as antimalarial agents.
Some of these compounds have been tested against multi-drug
resistant malaria in mice and have shown promising antimalarial
activity. The invention, thus relates to pharmaceutical
industry.
[0009] The trioxanes of the general formula 7 are new chemical
entities and they have not been prepared earlier.
[0010] The main objective of the present invention is to provide
novel substituted 1,2,4-trioxanes.
[0011] The objective of the present invention is also to provide a
process for the preparation of novel substituted 1,2,4-trioxanes of
general formula 7, a new series of antimalarial agents.
Accordingly, the present invention provides a process for the
preparation of novel substituted 1,2,4-trioxanes of general formula
7 as given below. 5
[0012] Wherein R represents cycloalkyl groups selected from the
groups consisting of cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and
4-chlorophenyl, R.sub.1 and R.sub.2 represent hydrogen, alkyl group
selected from methyl, ethyl, propyl and decyl, aryl selected from
phenyl or parts of a cyclic systems such as cyclopentane,
cyclohexane, substituted cyclohexane, cycloheptane, bicyclo (2.2.1)
heptane, adamantane which comprises reacting aryl methyl ketone of
formula 1, wherein R represents cycloalkyl groups selected from the
groups consisting of cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl or aryl groups selected from phenyl, 4-bromophenyl and
4-chlorophenyl with haloacetate such as ethyl bromoacetate or
ethylchloroacetate and Zn in presence of catalytic amount of
I.sub.2 in an aprotic organic solvent at a temperature range of
room temperature to refluxing temperature to give
.beta.-hydroxyester of formula 2, wherein R has the same meaning as
above, dehydrating the above said .beta.-hydroxy esters of formula
2 using a catalyst selected from the group consisting of I.sub.2,
P.sub.2O.sub.5, PTSA and cation exchanger such as Amberlyst-15, in
an aprotic organic solvent at room temperature to refluxing
temperature to obtain .alpha.,.beta.-unsaturated ester 3, wherein R
has the same meaning as above, reducing the above said esters of
formula 3 with a metal hydride such as LiAlH.sub.4 in an ether
solvent at a temperature ranging from 0.degree. C. to refluxing
temperature to give allylic alcohols of the formula 4, wherein R
has the same meaning as above, photooxygenating the above said
allylic alcohols of formula 4 in presence of a sensetizer in an
organic solvent at temperature ranging from -10.degree. C. to room
temperature to obtain O-hydroxyhydroperoxides of formula 5, wherein
R has the same meaning as above, reacting in situ or after
isolating the .beta.-hydroxyhydroperoxide of the formula 5 with an
aldehyde or ketone of the general formula 6, wherein, R.sub.1 and
R.sub.2 represent hydrogen, alkyl group such as methyl, ethyl,
propyl and decyl, aryl such as phenyl and parts of a cyclic system
selected from groups consisting of cyclopentane, cyclohexane,
cycloheptane, substituted cyclohexanes, bicyclo(2.2.1)heptane,
adamantane, in presence of an acid catalyst in an aprotic organic
solvent at a temperature range of 0.degree. C. to room temperature,
followed by isolation and purification by known methods to furnish
the trioxanes of general formula 7, wherein R, R.sub.1 and R.sub.2
have the same meaning as above.
[0013] In the process aryl methyl ketone of formula 1 are reacted
with haloacetate such as ethyl bromoacetate or ethylchloroacetate
and Zn in presence of catalytic amount of I.sub.2 in an aprotic
organic solvent such as benzene, toluene, diethyl ether, THF to
furnish .beta.-hydroxy ester of formula 2.
[0014] These .beta.-hydroxy esters of formula 2 can be isolated and
purified by standard laboratory methods such as column
chromatography or crystallization or can be used without
purification in the next step. .beta.-Hydroxy esters of formula 2
except compound 2e (formula 2, R=Ph) are new compounds and they
have not been prepared earlier. .beta.-Hydroxy ester 2e (formula 2,
R=Ph) is a known compound [Farmaco. Ed. Sci 1978,33(12), 992-8
(Ital)].
[0015] In the process dehydration of .beta.-hydroxy esters of
formula 2 may be effected in aprotic organic solvent such as
benzene, toluene, CHCl.sub.3 in the presence of a dehydrating
catalysts selected from I.sub.2, P.sub.2O.sub.5, p-toluene sulfonic
acid, H.sub.2SO.sub.4 or Amberlyst-15 (cation exchanger) to furnish
.alpha.,.beta.-unsaturated esters of formula 3. These unsaturated
esters can be isolated and purified by standard laboratory methods
such as column chromatography or crystallization. The
.alpha.,.beta.-unsaturated esters of formula 3 except compound 3e
(formula 3, R=Ph) are new compounds and they have not been prepared
earlier. .alpha.,.beta.-unsaturated ester of formula 3e (formula 3,
R=Ph) is a known compound [Chemical Abstract, 1976,
86,P106177d].
[0016] In the process reduction of .alpha.,.beta.-unsaturated
esters of formula 3 is effected with a complex metal hydride such
as LiAlH.sub.4 in an ether solvent such as diethyl ether,
tetrahydrofuran, to famish allylic alcohol of the formula 4. These
allylic alcohols of formula 4 can be isolated and purified by
standard laboratory methods such as crystallization or column
chromatography. The allylic alcohols of formula 4 are new compounds
and they have not been prepared earlier.
[0017] In the process photooxygenation of allylic alcohols of
formula 4 may be effected by passing oxygen gas or air in the
solution of the alcohol in an organic solvent and in the presence
of a dye and a light source which provides visible light for a
period in the range of 2 to 5 h, to furnish
.beta.-hydroxyhydroperoxides of formula 5. These
.beta.-hydroxyhydroperoxide of formula 5 which are new chemical
entities can be isolated and purified by standard laboratory
methods such as crystallization or column chromatography or can be
used in situ, without purification, in the next step. The dye which
acts as a sensitizer i.e. converts .sup.3O.sub.2 to highly reactive
.sup.1O.sub.2, may be selected from methylene blue, Rose Bengal,
tetraphenylporphine and the like. Organic solvent used may be
selected from CH.sub.2Cl.sub.2, benzene, CH.sub.3CN, acetone,
ethanol and the like.
[0018] In the process reaction of .beta.-hydroxyhydroperoxide of
formula 5 with aldehyde/ketones of formula 6 is done in an aprotic
solvent in the presence of an acid catalyst to furnish trioxanes of
formula 7. The aldehyde and ketones used may be such as
benzaldehyde, acetone, ethyl methyl ketone, methyl propyl ketone,
decyl methyl ketone, cyclopentanone, cyclohexanone, and bicyclic
ketone such as norcamphor and tricyclic ketones such as
2-adamantanone. The acid catalyst used may be such as HCl,
p-toluenesulfonic acid, H.sub.2SO.sub.4, acidic resin like
Amberlyst-15. The aprotic solvents used may be such as
CH.sub.2Cl.sub.2, CHCl.sub.3, benzene, CH.sub.3CN. These trioxanes
of formula 7 can be isolated and purified by standard laboratory
methods such as column chromatography and crystallization. These
trioxanes are new chemical entities and they have not been prepared
earlier. Some of the trioxanes of formula 7 have been tested
against malarial parasites in mice and show promising antimalarial
activity.
[0019] The invention is further illustrated by the following
examples which should not, however, be construed to limit the scope
of the present invention.
EXAMPLE 1
[0020] Ethyl 3-hydroxy-3-(4'-cyclopentylphenyl)-butanoate (Compound
2a, Formula 2, R=Cyclopentyl)
[0021] To a refluxing mixture of 4'-cyclopentylacetophenone (17 g),
I.sub.2 (5 mg) and Zn dust (12 g) in benzene (150 ml) was added
ethylbromoacetate (11 ml) dropwise over 30 minutes. The mixture was
refluxed for next 45 min and then cooled to room temperature. It
was acidified with 10% aqueous HCl solution (150 ml) and organic
layer was separated out. The organic layer was washed with water,
dried (Na.sub.2SO.sub.4) and concentrated. The crude product was
purified by column chromatography on silica gel to furnish 22 g
(88.1% yield) of ethyl 3-hydroxy-3-(4'-cyclopentylphenyl)-butanoate
(2a) as oil.
[0022] Ethyl 3-(4'-cyclopentylphenyl)-but-2-enoate (Compound 3a,
Formula 3, R=Cyclopentyl)
[0023] To a solution of ethyl
3-hydroxy-(4'-cyclopentylphenyl)-butanoate (2a, 12 g) in benzene
(150 ml) was added p-toluenesulfonic acid and refluxed for 1 h. The
mixture was diluted with sat. NaHCO.sub.3 (100 ml) and organic
layer was separated. The organic phase was washed with water, dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was purified
by column chromatography on silica gel to give 8.9 g (79.4% yield)
of ethyl 3-(4-cyclopentylphenyl)-but-2-enoate (3a, formula 3,
R=cyclopentyl) as oil.
[0024] 3-(4'-cyclopentylphenyl)-2-butenol (Compound 4a, Formula 4,
R=Cyclopentyl)
[0025] To an ice cooled slurry of LiAlH.sub.4 (2.7 g) in dry ether
(150 ml) was added a solution of ethyl
3-(4'-cyclopentylphenyl)-but-2-enoate (3a, 8.2 g) in dry ether (50
ml) dropwise. The mixture was stirred at 0.degree. C. for 3 h. The
reaction mixture was quenched with water (10 ml). A solution of 10%
NaOH (5 ml) was added and then ether layer was decanted. The
precipitate was washed with ether and combined organic layer was
concentrated. The crude product was purified by column
chromatography on silica gel to give 5.6 g (82.3% yield) of
3-(4'-cyclopentylphenyl)-2-butenol (4a, formula 4, R cyclopentyl)
as oil.
[0026] 3-(4'-cyclopentylphenyl)-1-hydroxy-but-3-en-2-hydroperoxide
(Compound 5a, Formula 5, R=Cyclopentyl)
[0027] A solution of 3-(4'-cyclopentylphenyl)-2-butenol (4a, 500
mg) and methylene blue (5 mg) in CH.sub.2Cl.sub.2 (30 ml) was
irradiated with a 250-watt tungsten-halogen lamp at -10.degree. C.
while oxygen was passed through the reaction mixture for 5 h. The
reaction mixture was concentrated under reduced pressure at r.t.
and purified by column chromatography on silica gel to furnish 0.29
g (51.7% yield) of hydroperoxide 5a as a solid m.p. 95-97.degree.
C.
[0028]
8-[(4-cyclopentylphenyl)vinyl]-6,7,10-trioxaspiro-[4,5]-decane
(Trioxane 7aa, Formula 7, R=Cyclopentyl; R.sub.1,
R.sub.2=--CH.sub.2CH.su- b.2CH.sub.2CH.sub.2)
[0029] A solution of 3-(4'-cyclopentylphenyl)-2-butenol (4a, 500
mg) and methylene blue (5 mg) in CH.sub.3CN (30 ml) was
photooxygenated at -10.degree. C. for 3 h. Cyclopentanone (1.5 ml)
and p-toluenesulfonic acid (50 mg) were added and reaction mixture
was left at r.t. for 20 h. Reaction mixture was concentrated to
remove CH.sub.3CN under reduced pressure, diluted with NaHCO.sub.3
(5 ml) and water (50 ml), extracted with ether (3.times.50 ml),
dried over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified by chromatotron on silica gel to furnish 0.38 g (52.7%
yield based on allylic alcohol, 4a used) of trioxane 7aa as
oil.
EXAMPLE 2
[0030] Trioxane 8a, Formula 8, R=Cyclopentyl
[0031] A solution of 3-(4'-cyclopentylphenyl)-2-butenol (4a, 320
mg) and methylene blue (5 mg) in CH.sub.3CN (25 ml) was
photooxygenated at -10.degree. C. for 4 h. Norcamphor (800 mg) and
p-toluenesulfonic acid (60 mg) were added and reaction mixture was
stirred for 20 h at r.t. The reaction mixture was worked up as
above and concentrated. Crude product was purified by chromatotron
on silica gel to furnish 0.14 g (28% yield based on allylic alcohol
4a, used) of trioxane 8a, m.p. 91-93.degree. C.
EXAMPLE 3
[0032] Trioxane 9a, Formula 9, R=Cyclopentyl
[0033] A solution of 3-(4'-cyclopentylphenyl)-2-butenol (4a, 500
mg) and methylene blue (5 mg) in CH.sub.3CN (30 ml) was
photooxygenated at -10.degree. C. for 3 h. 2-Adamantanone (500 mg)
and p-toluenesulfonic acid (50 mg) were added and reaction mixture
was stirred for 3.5 h at r.t. The reaction mixture was worked up as
above and concentrated. Crude product was purified by chromatotron
on silica gel to furnish 430 mg (49.4% yield, based on allylic
alcohol, 4a used) of trioxane 9a, m.p. 74-76.degree. C.
EXAMPLE 4
[0034] Trioxane 7ab, Formula 7, R=Cyclopentyl; R.sub.1,
R.sub.2=--CH.sub.2CH.sub.2CH(Ph)CH.sub.2CH.sub.2--
[0035] A solution of 3-(4-cyclopentylphenyl)-2-butenol (4a, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -10.degree. C. for 3 h. 4-Phenylcyclohexanone (1 g) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
stirred for 20 h at r.t. Reaction mixture was worked up as above
and concentrated. Crude product was purified by chromatotron on
silica gel to furnish 500 mg (60.2% yield, based on allylic
alcohol, 4a used) of trioxane 7ab, m.p. 98-100.degree. C.
EXAMPLE 5
[0036] Ethyl 3-hydroxy-3-(4'-cyclohexylphenyl)-butanoate (Compound
2b, Formula 2, R=Cyclohexyl)
[0037] To a refluxing mixture of 4'-cyclohexylacetophenone (25 g),
I.sub.2 (5 mg) and Zn (17 g) in benzene (150 ml) was added
ethylbromoacetate (20.7 ml) dropwise during 30 minutes. The mixture
was refluxed for 2 h and then cooled to room temperature. It was
acidified with 10% HCl (200 ml) an organic layer separated out. The
organic phase was washed with water, dried (Na.sub.2SO.sub.4) and
concentrated. The crude product was purified by column
chromatography using SiO.sub.2 as adsorbent and hexane-ethylacetate
mixture as eluant to give 28 g (80% yield) of ethyl
3-hydroxy-3-(4-cyclohexylphenyl)-butanoate (2b, formula 2,
R=cyclohexyl) m.p. 45.degree. C.
[0038] The above compound was also prepared using different
reaction condition. Table 1 gives the condition used and yield of
compound 2b.
1 TABLE 1 Solvent Temperature Reaction time Yield Diethyl ether
r.t. No reaction -- Diethyl ether Refluxed No reaction -- Toluene
Refluxed 30 minutes 90%
[0039] Ethyl 3-(4'-cyclohexylphenyl)-but-2-enoate (Compound 3b,
R=Cyclohexyl)
[0040] To a solution of ethyl
3-hydroxy-3-(4'-cyclohexylphenyl)-butanoate (2b, 29.5 g) in benzene
(80 ml) was added p-toluenesulfonic acid (1.8 g) and was refluxed
for 2 h. The reaction mixture was diluted with sat. NaHCO.sub.3,
benzene layer separated out. The organic layer was washed with
water, dried (Na.sub.2SO.sub.4) and concentrated. The crude product
was purified by column chromatography on silica gel to give 12.7 g
(46.01% yield) of ethyl
3-hydroxy-3-(4'-cyclohexylphenyl)-but-2-enoate (3b, formula 3,
R=cyclohexyl) as oil.
[0041] The compound 3b was also prepared using different reaction
condition. Table 2 gives the conditions used and the yield of
compound 3b.
2TABLE 2 Acid catalyst Solvent Temperature Reaction time Yield (%)
P.sub.2O.sub.5 Toluene Refluxed 1 h 65.2 Amberlyst-15 Toluene
Refluxed 1 h 35.1 I.sub.2 Benzene Refluxed 1.5 h 95.6
H.sub.2SO.sub.4 CHCl.sub.3 r.t. 36 h 29.0
[0042] 3-(4-cyclohexylphenyl)-2-butenol (Compound 4b, Formula 4,
R=Cyclohexyl)
[0043] To an ice-cooled slurry of LiAlH.sub.4 (3.8 g) in dry ether
(200 ml) was added a solution of ethyl
3-(4'-cyclohexylphenyl)-but-2-enoate (3b, 12.7 g) in dry ether (50
ml) dropwise. The reaction mixture was stirred for 3 h at 0.degree.
C. The reaction mixture was quenched with water (20 ml). A solution
of 10% NaOH (10 ml) was added and the ether layer was decanted. The
precipitate was washed with ether and combined extracts were
concentrated. The crude product was purified by column
chromatography on silica gel as adsorbent and hexane/ethylacetate
as eluant to furnish 9.5 g (88.7% yield) of
3-(4'-cyclohexylphenyl)-2-buteno- l (4b) m.p. 54-55.degree. C.
[0044] The LiAlH.sub.4 reduction of ethyl
3-(4'-cyclohexylphenyl)-but-2-en- oate (3b) using THF as solvent
under refluxing conditions did not provide the desired
compound.
[0045] 3-(4-cyclohexylphenyl)-1-hydroxy-but-3-en-2-hydroperoxide
(Compound 5b, Formula 5, R=Cyclohexyl)
[0046] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 600 mg)
and methylene blue (20 mg) in acetonitrile (35 ml) was irradiation
with a 250-watt tungsten-halogen lamp at -6.degree. C. while oxygen
was passed through the reaction mixture for 5 h. The crude product
obtained by usual aqueous workup was crystallized from
CH.sub.2Cl.sub.2 to give 80 mg of hydroperoxide 5b. The filtrate
was chromatographed on silica gel to give 400 mg of hydroperoxide
5b. The combined yield of hydroperoxide (compound 5b, formula 5,
R=cyclohexyl) was 480 mg (70% yield), m.p. 95-97.degree. C.
[0047] Photooxygenation of 3-(4-cyclohexylphenyl)-2-butenol (4b) in
benzene at -6.degree. C. using tetraphenylphorphine as sensitizer
furnished the above hydroperoxide 5b in 85.2% yield.
[0048] 3,3-dimethiyl-6-[4'-cyclohexylphfenylivinyl-1,2,4-trioxane
(Trioxane 7ba, Formula 7, R=Cyclohexyl)
[0049] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (50 mg) in acetone (30 ml) was photooxygenated
at -6.degree. C. for 3 h to give compound 5b (as shown by TLC). To
the mixture was added p-toluenesulfonic acid (60 mg) and stirred
for 3 h at r.t. The reaction mixture was worked up as above and
concentrated. The crude product was purified by column
chromatography on silica gel to furnish 500 mg (76.9% yield based
on allylic alcohol, 4b used) of trioxane 7ba, m.p. 54-55.degree.
C.
EXAMPLE 6
[0050]
3-decyl,3-methyl-6-[(4'-cyclohexylphenyl)vinyl-1,2,4-trioxane
(Trioxane 7bb, Formula 7, R=Cyclohexyl)
[0051] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -6.degree. C. for 3 h. 2-Dodecanone (1 ml) and p-toluenesulfonic
acid were added and reaction mixture was stirred at r.t for 18 h.
The reaction mixture was worked up as above and concentrated. The
crude product was purified by chromatotron on silica gel to furnish
290 mg (31.1% yield, based on allylic alcohol, 4b used) of trioxane
7bb as oil.
EXAMPLE 7
[0052] 6[(4'-cyclohiexylphenyl)vinyl]-3-phenyl-1,2,4-trioxane
(Trioxane 7bc, Formula 7, R=Cyclohexyl]
[0053] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (25 ml) was photooxygenated
at 6.degree. C. for 2.5 h. Benzaldehyde (1 ml) and
p-toluenesulfonic acid (50 mg) were added and the mixture was left
at r.t. for 18 h. Reaction mixture was worked up and crude product
was purified by flash column chromatography on silica gel to
furnish 340 mg (44.7% yield based on allylic alcohol, 4b used) of
trioxane 7bc, m.p. 86-88.degree. C.
EXAMPLE 8
[0054] 3[(4'-cyclohexylphenyl)vinyl]-1,2,5-trioxaspiro(5,5)undecane
(Trioxane 7bd, Formula 7, R=Cyclohexyl,
R.sub.1R.sub.2=--CH.sub.2CH.sub.2- CH.sub.2CH.sub.2CH.sub.2--)
[0055] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at 6C for 3 h. Cyclohexanone (1.5 ml) and p-toluenesulfonic acid
(50 mg) were added and the mixture was stirred for 4 h. The
reaction mixture was worked up and crude product was purified by
flash column chromatography on silica gel to furnish 550 mg (74.3%
yield based on allylic alcohol, 4b used) of trioxane 7bd, m.p.
60-62.degree. C.
EXAMPLE 9
[0056] Trioxane 8b, Formula 8, R=Cyclohexyl
[0057] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -8.degree. C. for 4 h. Norcamphor (1 g) and p-toluenesulfonic
acid (50 mg) were added and the mixture was left at 5.degree. C.
for 16 h. The reaction mixture was worked up and the crude product
was purified by flash column chromatography on silica gel to
furnish 300 mg (40.8% yield based on allylic alcohol, 4b used) of
trioxane 8b, m.p. 70-71.degree. C.
EXAMPLE 10
[0058] Trioxane 9b, Formula 9, R=Cyclohexyl
[0059] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (50 ml) was photooxygenated
at -6.degree. C. for 3 h. 2-Adamantanone (1 g) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
stirred at r.t. for 2 h. and then left unstirred at 5.degree. C.
for 15 h. Reaction mixture was worked up and crude product was
purified by column chromatography on silica gel to furnish 500 mg
(58.8% yield based on allylic alcohol, 4b used) of trioxane 9b,
m.p. 75-76.degree. C. Trioxane 9b was also prepared by the
following method using purified hydroperoxide 5b.
[0060] To a solution of hydroperoxide 5b (290 mg) and
2-adamantanone (300 mg) in CHCl.sub.3 (20 ml) was added one drop
conc. H.sub.2SO.sub.4 and the reaction was kept at r.t. for 14 h.
The reaction mixture was diluted with sat. NaHCO.sub.3 (5 ml) and
water (10 ml), extracted with ether (2.times.20 ml), dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by chromatotron on silica gel to furnish 250 mg (49.0% yield) of
trioxane 9b, m.p. 75-76.degree. C.
[0061] The above trioxane was also prepared using different
reaction conditions. Table 3 gives the conditions used and the
yields of the trioxane 9b.
3TABLE 3 Temp- Reaction Dye erature Solvent Acid catalyst time
Yield Tetraphenyl- -10.degree. C. CH.sub.2Cl.sub.2 HCl 18 h 52.9%
Porphine Rose Bengal r.t. EtOH * Amberlyst-15 18 h 56.8% * EtOH was
removed under reduced pressure after photooxygenation and replaced
by CH.sub.2Cl.sub.2 in the second step before the addition of
2-Adamantanone.
EXAMPLE 11
[0062] Trioxane 7be, Formula 7, R=Cyclohexyl,
R.sub.1R.sub.2=--CH.sub.2--C- H.sub.2--CH(Ph)CH.sub.2CH.sub.2--
[0063] A solution of 3-(4'-cyclohexylphenyl)-2-butenol (4b, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -10.degree. C. for 2.5 h. 4-Phenylcyclohexanone (1 g) and
p-toluenesulfonic acid (50 mg) were added and the reaction mixture
was left at r.t. for 20 h. The reaction mixture was worked up as
above and concentrated. The crude product was purified by column
chromatography on silica gel to furnish 570 mg (63.3% yield based
on allylic alcohol 4b, used) of trioxane 7be as a mixture of two
stereoisomers m.p. 107-109.degree. C.
EXAMPLE 12
[0064] Ethyl 3-hydroxy-3-(4'-cycloheptylphenyl)-butanoate (Compound
2c, Formula 2, R=Cycloheptyl)
[0065] To a refluxing mixture of 4-cycloheptylacetophenone (25 g),
I.sub.2 (5 mg) and Zn (15 g) in benzene (200 ml) was added
ethylbromoacetate (15 ml) dropwise during 1 h. The mixture was
refluxed for 4.5 h and then cooled to room temperature. It was
acidified with 10% HCl (200 ml) and benzene layer separated out.
The organic layer was washed with water, dried (Na.sub.2SO.sub.4)
and concentrated. The crude product was purified by column
chromatography on silica gel to give 30.9 g (87.8% yield) of ethyl
3-hydroxy-3-(4'-cycloheptylphenyl)-butanoate (2c formula 2,
R=cycloheptyl) as viscous oil.
[0066] Ethyl 3-(4'-cycloheptylphenyl)-but-2-enoate (Compound 3c,
Formula 3, R=Cycloheptyl)
[0067] To a solution of ethyl
3-hydroxy-3-(4'-cycloheptylphenyl)-butanoate (2c, 28.75 g) in
benzene (175 ml) was added p-toluenesulfonic acid and was refluxed
for 1 h. The reaction mixture was diluted with NaHCO.sub.3 and
benzene layer was separated out. The organic layer was washed with
water, dried (Na.sub.2SO.sub.4) and concentrated. The crude product
was purified by column chromatography on silica gel to give 11.6 g
(42.9% yield) of ethyl 3-(4'-cycloheptylphenyl)-but-2-enoate (3c,
formula 3, R=cycloheptyl) as viscous oil.
[0068] 3-(4'-cycloheptylphenyl)-2-butenol (Compound 4c, Formula 4,
R=Cycloheptyl)
[0069] To an ice cooled slurry of LiAlH.sub.4 (2.7 g) in dry ether
(175 ml) was added a solution of ethyl
3-(4'-cycloheptylphenyl)-but-2-enoate (3c, 9.5 g) in dry ether (50
ml) dropwise. The mixture was stirred for 4 h. at 0.degree. C. The
reaction mixture was quenched with water (7 ml). A solution of 10%
NaOH (3 ml) was added. The precipitate was washed with ether and
combined ether extract was dried (Na.sub.2SO.sub.4) and
concentrated. Crude product was purified by column chromatography
on silica gel to give 6.1 g (75.3% yield) of allylic alcohol (4c,
formula 4, R cycloheptyl) as oil.
[0070] 3-(4'-cycloheptylphenyl)-1-hydroxy-but-3-en-2-hydroperoxide
(Compound 5c, Formula 5, R=Cycloheptyl)
[0071] A solution of 3-(4'-cycloheptylphenyl)-2-butenol (4c, 150
mg) and methylene blue (2 mg) in acetonitrile (10 ml) was
irradiated with a 250-watt tungsten-halogen lamp at -6.degree. C.
while oxygen was passed through the reaction mixture for 2.5 h. The
reaction mixture was concentrated and crude product was purified by
column chromatography on silica gel to furnish 120 mg (75% yield)
of hydroperoxide 5c, m.p. 106-108.degree. C.
[0072]
3-[(4'-cycloheptylphenyl)vinyl]-1,2,5-trioxaspiro-[5,5]-undecane
(Trioxane 7ca, Formula 7, R=Cycloheptyl; R.sub.1,
R.sub.2=--CH.sub.2CH.su- b.2CH.sub.2CH.sub.2CH.sub.2--)
[0073] A solution of 3-(4'-cycloheptylphenyl)-2-butenol (4c, 1 g)
and methylene blue (5 mg) in CH.sub.3CN (50 ml) was photooxygenated
at -10.degree. C. for 3 h. Cyclohexanone (3 ml) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
stirred for 18 h at r.t. The reaction mixture was worked up as
above and concentrated. Crude product was purified by
chromatography on silica gel to give 700 mg (50% yield, based on
allylic alcohol, 4c used) of trioxane 7ca m.p. 55-57.degree. C.
EXAMPLE 13
[0074] Trioxane 8c, Formula 8, R=Cycloheptyl
[0075] A solution of 3-(4'-cycloheptylphenyl)-2-butenol (4c, 500
mg) and methylene blue (5 mg) in CH.sub.3CN (30 ml) was
photooxygenated at -6.degree. C. for 3.5 h. Norcamphor (500 mg) and
p-toluenesulfonic acid (30 mg) were added and reaction mixture was
stirred for 18 h. at r.t. The reaction mixture was worked up as
above and concentrated. Crude product was purified by chromatotron
on silica gel to furnish 290 mg (38.6% yield, based on allylic
alcohol, 4c used) of trioxane 8c m.p. 65-68.degree. C.
EXAMPLE 14
[0076] Trioxane 9c, Formula 9, R=Cycloheptyl
[0077] A solution of 3-(4'-cycloheptylphenyl)-2-butenol (4c, 500
mg) and methylene blue (5 mg) in CH.sub.3CN (30 ml) was
photooxygenated at -6.degree. C. for 2 h. 2-Adamantanone (600 mg)
and p-toluenesulfonic acid (50 mg) were added and reaction mixture
was stirred for 22 h. at r.t. The reaction mixture was worked up as
above and concentrated. Crude product was purified by chromatotron
on silica gel to furnish 420 mg (50.6% yield, based on allylic
alcohol, 4c used) of trioxane 9c as oil.
EXAMPLE 15
[0078] Trioxane 7cb, Formula 7, R=Cycloheptyl;
R.sub.1R.sub.2=--CH.sub.2---
CH.sub.2--CH[C(CH.sub.3).sub.2CH.sub.2CH.sub.3]--CH.sub.2CH.sub.2--
[0079] A solution of 3-(4'-cycloheptylphenyl)-2-butenol (4c, 500
mg) and methylene blue (5 mg) in CH.sub.3CN (30 ml) was
photooxygenated at -6.degree. C. for 3 h. 4-t-Amylcyclohexanone
(1.5 ml) and p-toluenesulfonic acid (50 mg) were added and reaction
mixture was stirred for 18 h. at r.t. The reaction mixture was
worked up as above and concentrated. Crude product was purified by
chromatotron on silica gel to furnish 400 mg (45.9% yield, based on
allylic alcohol, 4c, used) of trioxane 7cb m.p. 58-60.degree.
C.
EXAMPLE 16
[0080] Ethyl 3-hydroxy-3-(4'-cyclooctylphenyl)-butanoate (Compound
2d, Formula 2, R=Cyclooctyl)
[0081] To a refluxing mixture of 4'-cyclooctylacetophenone (30 g),
I.sub.2 (5 mg) and Zn (17.2 g) in benzene (300 ml) was added
ethylbromoacetate (18 ml) dropwise during 30 minutes. The mixture
was refluxed for 2 h and then cooled to room temperature. It was
acidified with 10% HCl (200 ml), benzene layer was separated out.
The organic layer was washed with water, dried (Na.sub.2SO.sub.4)
and concentrated. The crude product was purified by column
chromatography on silica gel to give 39.4 g (95% yield) of ethyl
3-hydroxy-3-(4'-cyclooctylphenyl)-butanoate (2d, formula 2,
R=cyclooctyl) as viscous oil.
[0082] Ethyl 3-(4'-cyclooctylphenyl)-but-2-enoate (Compound 3d,
Formula 3, R=Cyclooctyl)
[0083] To a solution of ethyl
3-hydroxy-3-(4'-cyclooctylphenyl)-butanoate (2d, 36 g) in benzene
(350 ml) was added p-toluenesulfonic acid and refluxed for 2.5 h.
The mixture was diluted with saturated NaHCO.sub.3 solution (20 ml)
and water (50 ml) and benzene layer was separated out. Aqueous
layer was extracted with benzene (2.times.200 ml) combined organic
layer was washed with water (2.times.20 ml), dried over
Na.sub.2SO.sub.4 and concentrated. Crude product was purified by
column chromatography to furnish 27.5 g (81.1% yield) of ethyl
3-(4'-cyclooctylphenyl)-but-2-enoate (3d, formula 3, R=cyclooctyl)
as oil.
[0084] 3-(4'-cyclooctylphenyl)-2-butenol (Compound 4d, Formula 4,
R=Cyclooctyl)
[0085] To an ice cooled slurry of LiAlH4 (2.9 g) in dry ether (200
ml) was added a solution of ethyl
3-(4'-cyclooctylphenyl)-but-2-enoate (3d, 10 g) in dry ether (50
ml) dropwise. The reaction mixture was stirred at 0.degree. C. for
2 h. The reaction mixture was quenched with water (11 ml). A
solution of 10% NaOH (10 ml) was added and ether layer was
decanted. The precipitate was washed with ether and combined
extracts were concentrated. The crude product was purified by
column chromatography on silica gel to give 6.82 g (79.3% yield) of
3-(4'-cyclooctylphenyl)-2-butenol (4d, formula 4,R=cyclooctyl) m.p.
40-44.degree. C.
[0086] 3-(4'-cyclooctylphenyl)-1-hydroxy-but-3-en-2-hydroperoxide
(Compound 5d, Formula 5, R=Cyclooctyl)
[0087] A solution of 3-(4'-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was irradiation
with a 250-watt tungsten-halogen lamp at 6.degree. C. while oxygen
was passed through the reaction mixture. After 2.5 h the reaction
mixture was concentrated and crude product was purified by column
chromatography on silica gel to furnished 400 mg (71.4% yield),
m.p. 83-85.degree. C.
[0088]
3-ethyl-3-methyl-6-[(4'-cyclooctylphenyl)vinyl]-1,2,4-trioxane
(Compound 7da, Formula 7, R=Cyclooctyl)
[0089] A solution of 3-(4'-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -6.degree. C. for 3 h. Ethyl methyl ketone (1 ml) and HCl (1
drop) were added and the reaction mixture was left at r.t. for 18
h. The reaction mixture was concentrated to remove CH.sub.3CN,
diluted with NaHCO.sub.3 and water and extracted with ether
(3.times.30 ml). The organic layer was dried over Na.sub.2SO.sub.4
and concentrated. The crude product was purified by chromatotron
over silica gel to give 190 mg (28.7% yield based on allylic
alcohol, 4d, used) of trioxane 7da as oil.
EXAMPLE 17
[0090]
3-[(4-cyclooctylphenyl)vinyl]-1,2,5-trioxaspiro-(5,5)-undecane
(Trioxane 7 db, Formula 7, R=Cyclooctyl; R.sub.1,
R.sub.2=--CH.sub.2CH.su- b.2CH.sub.2CH.sub.2CH.sub.2--)
[0091] A solution of 3-(4-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -6.degree. C. for 2.5 h. Cyclohexanone (1.5 ml) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
left at r.t. for 18 h. The reaction mixture was worked up as above
and concentrated. The crude product was purified by chromatron on
silica gel to give 340 mg (47.8% yield, based on allylic alcohol,
4d used) of trioxane 7 db as solid m.p. 58-60.degree. C.
EXAMPLE 18
[0092]
3-[(4'-cyclooctylphenyl)vinyl]-1,2,5-trioxaspiro-(6,5)-dodecane
(Trioxane 7dc, R=Cyclooctyl;
R.sub.1R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.-
sub.2CH.sub.2CH.sub.2--)
[0093] A solution of 3-(4'-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -6.degree. C. for 2.5 h. Cycloheptanone (1.5 ml) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
left at r.t. for 18 h. The reaction mixture was worked up as above
and concentrated. The crude product was purified by chromatotron on
silica gel to furnish 210 mg (28.3% yield, based on allylic
alcohol, 4d used) of trioxane 7dc as oil.
EXAMPLE 19
[0094] Trioxane 7dd, Formula 7, R=Cyclooctyl; R.sub.1,
R.sub.2=--CH.sub.2CH.sub.2CH(Ph)CH.sub.2CH.sub.2--)
[0095] A solution of 3-(4'-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -8.degree. C. for 2.5 h. 4-Phenylcyclohexanone (1 g) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
left at r.t. for 18 h. The reaction mixture was worked up as above
and concentrated. The crude product was purified by chromatotron on
silica gel to furnish 340 mg (39.5% yield, based on allylic
alcohol, 4d used) of trioxane 7dd as solid m.p. 95-97.degree.
C.
EXAMPLE 20
[0096] Trioxane 8d, Formula 8, R=Cyclooctyl
[0097] A solution of 3-(4'-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -6.degree. C. for 2.5 h. Norcamphor (500 mg) and
p-toluenesulfonic acid (50 mg) were added and reaction mixture was
kept at 110.degree. C. for 48 h. Reaction mixture was worked up as
above and concentrated. Crude product was purified by chromatotron
on silica gel to furnish 350 mg (47.5% yield, based on allylic
alcohol 4d, used) of trioxane 8d as oil.
EXAMPLE 21
[0098] Trioxane 9d, Formula 9, R=Cyclooctyl
[0099] A solution of 3-(4'-cyclooctylphenyl)-2-butenol (4d, 500 mg)
and methylene blue (5 mg) in CH.sub.3CN (30 ml) was photooxygenated
at -10.degree. C. for 3 h. 2-Adamantanone (500 mg) and
p-toluenesulfonic acid (80 mg) were added and reaction mixture was
stirred at r.t. for 4 h and then left at r.t. for 14 h. Reaction
mixture was worked up as above and concentrated. Crude product was
purified by chromatotron on silica gel to furnish 360 mg (44.4%
yield, based on allylic alcohol 4d, used) of trioxane 9d as
oil.
EXAMPLE 22
[0100] Ethyl 3-hydroxy-3-([1,1'-biphenyl]-4yl)-butanoate (Compound
2e, Formula 2, R=Ph)
[0101] To a refluxing mixture of 4-acetylbiphenyl (20 g), I.sub.2
(5 mg) and Zn (6.8 g) in benzene (200 ml) was added
ethylbromoacetate (12 ml) dropwise during 30 minutes. The mixture
was refluxed for 1 h and then cooled to room temperature. It was
acidified with 10% HCl (100 ml) and benzene layer was separated
out. The organic layer was washed with water, dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was purified
by column chromatography on silica gel to give 20.6 g (72.1% yield)
of ethyl 3-hydroxy-3-([1,1-biphenyl]-4yl) butanoate (2e, formula 2,
R=Ph) m.p. 58-60.degree. C.
[0102] The above compound was also prepared using different
reaction condition. Table 4 gives the condition used and yield of
compound 2e.
4 TABLE 4 Solvent Temperature Reaction time Yield Diethyl ether
r.t. No reaction -- Diethyl ether Refluxed No reaction -- Toluene
Refluxed 1 h 92.8%
[0103] The compound 2e was also prepared using ethylchloroacetate
under same reaction conditions to furnish 17.8% yield of ethyl
3-hydroxy-3-([1,1'-biphenyl]-4yl) butanoate (2e).
[0104] Ethyl 3-([1,1'-biphenyl]-4yl)-but-2-enoate (Compound 3e,
Formula 3, R=Ph)
[0105] To a solution of ethyl
3-hydroxy-3-([1,1'-biphenyl]-4yl)-butanoate (2e, 11 g) in benzene
(250 ml) was added phosphorus pentoxide (4 g) and refluxed for 3 h.
The benzene layer was decanted and then concentrated. The crude
product was purified by column chromatography on silica gel to
furnish 11 g (57.3% yield) of ethyl
3-([1,1'-biphenyl]-4yl)-but-2-enoate (3e, formula 3, R=Ph) m.p.
76-78.degree. C.
[0106] The compound 3e was also prepared using different reaction
condition. Table 5 gives the conditions used and the yield of
compound 3e.
5TABLE 5 Acid catalyst Solvent Temperature Reaction time Yield (%)
PTSA Benzene Refluxed 1 h 55.5 Amberlyst-15 Toluene Refluxed 1 h
77.7 I.sub.2 Benzene Refluxed 1 h 88.8 H.sub.2SO.sub.4 CHCl.sub.3
r.t. 18 h 33.3
[0107] 3-([,1,1'-biphenyl]-4yl)-2-butenol (Compound 4e, Formula 4,
R=Ph)
[0108] To an ice cooled slurry of LiAlH.sub.4 (4.0 g) in dry ether
(400 ml) was added ethyl 3-([1,1'-biphenyl]-but-2-enoate (3e, 11 g)
in dry ether (200 ml) dropwise. The mixture was stirred at
0.degree. C. for 2 h. The reaction mixture was quenched with water
(10 ml). A solution of 10% NaOH (5 ml) was added, stirred and then
ether layer was decanted. The precipitate was washed with ether and
combined ether extracts were concentrated. The crude product was
purified by chromatography on silica gel to give 7.2 g (77.4%
yield) of 3-([1,1'-biphenyl]-4yl)-2-butenol (4e formula 4, R=Ph),
m.p. 112-114.degree. C.
[0109] LiAlH.sub.4 reduction of ethyl
3-([1,1'-biphenyl]-but-2-enoate (3e) using THF as solvent under
similar conditions furnished 40.6% yield of
3-([1,1'-biphenyl]-4yl)-2-butenol (4e).
[0110] 3-([1,1'-biphenyl]-4yl)-1-hydroxy-but-3-en-2-hydroperoxide
(Compound 5e, Formula 5, R=Ph)
[0111] A solution of 3-([1,1'-biphenyl]-4yl)-2-butenol (4e, 200 mg)
and methylene blue (2 mg) in acetonitrile (15 ml) was irradiated
with 250-watt tungsten--halogen lamp at -6.degree. C. while oxygen
was passed through the reaction mixture. After 4 h the reaction
mixture was concentrated. The reaction mixture was filtered through
a cintered crucible to furnish 80 mg of hydroperoxide. Mother
liquor was purified by column chromatography to furnish 40 mg of
hydroperoxide. The combined yield of hydroperoxide (compound 5e,
formula 5, R=Ph) was 120 mg (54.5% yield) m.p. 124.degree. C.
[0112] Phototoxygenation of 3-([1,1'-biphenyl]-4yl)-2-butenol (4e),
in CHCl.sub.3 at 0.degree. C., using tetraphenylporphine as
sensetizer furnished 5e in 81.8% yield.
[0113] 6-[([1,1'-biphenyl]-4yl)vinyl]-3-phenyl-1,2,4-trioxane
(Trioxane 7ea, Formula 7, R=Ph, R.sub.1, R.sub.2=H, Ph).
[0114] To a solution of
3-([1,1'-biphenyl]-4yl)-1-hydroxy-but-3-en-2-hydro- peroxide (5e,
400 mg) and benzaldehyde (350 mg) in acetonitrile (10 ml) was added
p-toluenesulfonic acid (20 mg) and was stirred at r.t. for 2 h. The
reaction mixture was worked up as above and concentrated. Crude
product was purified by column chromatography to furnish 280 mg
(70% yield) of trioxane 7ea m.p. 110-112.degree. C.
EXAMPLE 23
[0115] 8-[([1,1'-biphenyl]-4yl)vinyl]-6,7,10-trioxaspiro (4,5)
Decane (Trioxane 7eb, Formula 7, R=Ph,
R.sub.1R.sub.2--CH.sub.2CH.sub.2CH.sub.2C- H.sub.2--)
[0116] To a solution of
3-(1,1-biphenyl]-4yl)-1-hydroxy-but-3-en-hydropero- xide (5e, 430
mg) and cyclopentanone (700 mg) in acetonitrile (10 ml) was added
p-toluenesulfonic acid (30 mg) and the reaction mixture was stirred
at r.t. for 3 h. The reaction mixture was worked up as above and
concentrated. The crude product was purified by column
chromatography followed by crystallization from hexane to furnish
250 mg (45.1% yield) of trioxane 7eb, m.p. 102-104.degree. C.
EXAMPLE 24
[0117] 3-[([1,1'-biphenyl]-4yl)vinyl]-1,2,5-trioxaspiro (5,5)
Undecane (Trioxane 7ec, Formula 7, R=Ph,
R.sub.1R.sub.2=--CH.sub.2CH.sub.2CH.sub.2- CH.sub.2CH.sub.2--)
[0118] To a solution of
3-([1,1'-biphenyl]-4yl)-1-hydroxy-but-3-en-2-hydro- peroxide (5e,
600 mg) and cyclohexanone (1 ml) in acetonitrile (20 ml) was added
p-toluenesulfonic acid (20 mg) and the reaction mixture was stirred
at r.t. for 1 h. The reaction mixture was worked up as above and
concentrated. The crude product was purified by column
chromatography followed by crystallization from hexane to furnish
360 mg (46.1% yield) of trioxane 7ec, m.p. 96-98.degree. C.
EXAMPLE 25
[0119]
3-decyl-3-methyl-6-[([1,1'-biphenyl]-4-yl)-vinyl]-1,2,4-trioxane
(Trioxane 7ed, Formula 7, R=Ph; R.sub.1, R.sub.2=CH.sub.3,
--CH.sub.2(CH.sub.2).sub.8CH.sub.3)
[0120] A solution of 3-([1,1'-biphenyl]-4yl)-2-butenol (4e, 200 mg)
and methylene blue (2 mg) in acetonitrile (10 ml) and chloroform
(10 ml) was photooxygenated at 0.degree. C. for 3 h. 2-dodecanone
(0.5 ml) and hydrochloric acid (2 drops) were added and reaction
mixture of left at r.t. for 18 h. The reaction mixture was worked
up and concentrated. Crude product was purified by column
chromatography on silica gel to furnish 100 mg mg (27% yield, based
on allylic alcohol, 4e, used) of trioxane 7ed m.p. 86-90.degree.
C.
EXAMPLE 26
[0121] Trioxane 8e, Formula 8, R=Ph
[0122] A solution of 3-([1,1'-biphenyl]-4yl)-2-butenol (4e, 200 mg)
and methylene blue (2 mg) in acetonitrile (15 ml) was
photooxygenated at -10.degree. C. for 3 h. Norcamphor (250 mg) and
p-toluene sulfonic acid (30 mg) were added and reaction mixture was
left at r.t. for 18 h. The reaction mixture was worked up and
concentrated. Crude product was purified by column chromatography
on silica gel to furnish 140 mg (45.1% yield, based on allylic
alcohol, 4e, used) of trioxane 8e m.p. 86-90.degree. C.
EXAMPLE 27
[0123] Trioxane 9e, Formula 9, R=Ph
[0124] To a solution of
3-([1,1'-biphenyl]-4yl)-1-hydroxy-but-3-en-2-hydro- peroxide (5e,
300 mg) and 2-Adamantanone (250 mg) in acetonitrile (20 ml) was
added p-toluenesulfonic acid (30 mg) and was stirred for 1 h at
r.t. The reaction mixture was worked up and concentrated. Crude
product was purified by column chromatography on silica gel to
furnish 320 mg (71.04% yield) of trioxane 9e, m.p. 94-96.degree.
C.
[0125] The above trioxane was also prepared from 4e using different
reaction conditions. Table 6 gives the conditions used and the
yields of the trioxane 9e.
6TABLE 6 Temp- Reaction Dye erature Solvent Acid catalyst time
Yield.sup.a Tetraphenyl- r.t. CHCl.sub.3 H.sub.2SO.sub.4 30 min
55.5% Porphine Rose Bengal -6.degree. C. EtOH * Amberlyst-15 2 h
24.4% * EtOH was removed under reduced pressure after
photooxygenation and replaced by CHCl.sub.3 in the second step
before the addition of 2-Adamantanone. .sup.aYields based on
allylic alcohols 4e used.
EXAMPLE 28
[0126] Ethyl 3-hydroxy-3-(4'-bromo[1,1'-biphenyl]-4-yl)-butanoate
(Compound 2f, Formula 2, R=p-Br--C.sub.6H.sub.4)
[0127] To a refluxing mixture of 4-(4'-bromophenyl)acetophenone (10
g), I.sub.2 (5 mg) and Zn (4.9 g) in benzene (100 ml) was added
ethylbromoacetate (6.1 ml) dropwise during 45 minutes. The mixture
was refluxed for 45 minutes and then cooled to room temperature. It
was acidified with 10% HCl (75 ml) and benzene layer was separated.
Organic layer was washed with water, dried (Na.sub.2SO.sub.4) and
concentrated. Crude product was crystallized from hexane to furnish
8 g of .beta.-hydroxyester (2f). Mother liquor was purified by
column chromatography on silica gel to furnish 3.7 g of
---hydroxyester (2f). The combined yield of ---hydroxyester
(compound 2f, formula 2, R=p-Br--C.sub.6H.sub.4) was 11.7 g
(88.9%), m.p. 70.degree. C.
[0128] Ethyl 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-but-2-enoate
(Compound 3f, Formula 3, R=p-Br--C.sub.6H.sub.4)
[0129] To a solution of ethyl
3-hydroxy-3-(4'-bromo[1,1'-biphenyl]-4-yl)-b- utanoate (2f, 8.0 g)
in benzene (75 ml) was added p-toluenesulfonic acid (420 mg) and
was refluxed for 1 h 15 minutes. The reaction mixture was cooled,
neutralized with NaHCO.sub.3 solution, diluted with water and
organic layer was extracted. Organic layer was washed with water,
dried (Na.sub.2SO.sub.4) and concentrated. Crude product was
purified by column chromatography on silica gel to furnish 5 g
(65.7% yield) of ethyl
3-hydroxy-3-(4'-bromo[1,1'-biphenyl]-4-yl)-but-2-enoate (3f,
formula 3, R=p-Br--C.sub.6H.sub.4) m.p. 96-98.degree. C.
[0130] 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-butenol (Compound 4f,
Formula 4, R=p-Br--C.sub.6H.sub.4)
[0131] To an ice cooled slurry of LiAlH.sub.4 (2.0 g) in dry ether
(200 ml) was added a solution of ethyl
3-hydroxy-3-(4'-bromo-[1,1'-biphenyl]-4- -yl)-but-2-enoate (3f, 4.4
g) in dry ether (100 ml) dropwise. The reaction mixture was stirred
for 5 h at 0.degree. C. The reaction mixture was quenched with
water (5 ml). A solution of 10% NaOH (5 ml) was added and the ether
layer was decanted. The precipitate was washed with ether and the
combined ether extract was concentrated. The crude product was
chromatographed on silica gel to give 2 g (52.6% yield) of
3-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-butenol (4f, formula 4,
R=p-Br--C.sub.6H.sub.4) m.p. 145-148.degree. C.
[0132]
3-(4'-bromo-([1,1'-biphenyl]-4yl)-1-hydroxy-but-3-en-2-hydroperoxid-
e (Compound 5f, Formula 5, R=p-Br--C.sub.6H.sub.4)
[0133] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-butenol
(4f, 100 mg) and methylene blue (5 mg) in acetonitrile (7 ml) and
CH.sub.2Cl.sub.2 (7 ml) was irradiated with a 250 watt
tungsten-halogen lamp at -6.degree. C. while oxygen was passed
through the reaction mixture for 5 h. The crude product obtained by
usual aqueous workup was crystallized from CH.sub.2Cl.sub.2 to give
20 mg of hydroperoxide 5f. The filtrate was chromatographed on
silica gel to give 40 mg of hydroperoxide 5f. The combined yield of
hydroperoxide (compound 5f, formula 5, R=p-Br--C.sub.6H.sub.4) was
60 mg (55% yield).
[0134]
3,3-dimethyl-6-[(4'-bromo-[1,1-biphenyl]-4-yl)-vinyl]-1,2,4-trioxan-
e (Trioxane 7fa, Formula 7, R=p-Br--C.sub.6H.sub.4; R.sub.1,
R.sub.2=CH.sub.3, CH.sub.3)
[0135] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-butenol
(4f, 350 mg) and methylene blue (2 mg) in acetone (40 ml) was
photooxygenated at -10.degree. C. for 5 h. To the mixture was added
p-toluenesulfonic acid (50 mg) and left at r.t. for 18 h and then
concentrated. The crude product was purified by column
chromatography to give 300 mg (69.7% yield) of trioxane 7fa m.p.
92-95.degree. C.
EXAMPLE 29
[0136]
3-ethyl-3-methly-6-[(4'-bromo-[1,1'-biphenyl]-4-yl)-vinyl]-1,2,4-tr-
ioxane (Trioxane 7fb, Formula 7, R=p-Br--C.sub.6H.sub.4; R.sub.1,
R.sub.2=CH.sub.3, CH.sub.2CH.sub.3)
[0137] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-butenol
(4f, 500 mg) and methylene blue (5 mg) in CH.sub.3CN (40 ml) and
CH.sub.2Cl.sub.2 was photooxygenated at -6.degree. C. for 3 h. To
the mixture was added ethyl methyl ketone (3 ml) and
p-toluenesulfonic acid (40 mg) and left at r.t. for 18 h. The
reaction mixture was diluted with saturated NaHCO.sub.3 solution (5
ml) and worked up as above and concentrated. The crude product was
purified by column chromatography to give 240 mg (37.5% yield) of
trioxane 7fb as a mixture of two stereoisomers, which were further,
purified to furnish the more polar isomer, m.p. 72-74.degree. C.
and less polar isomer, m.p. 82-85.degree. C.
EXAMPLE 30
[0138] 3-[(4'-bromo-[1,1'-biphenyl]-4-yl)-vinyl]-1,2,5-trioxaspiro
(5,5) Undecane (Trioxane 7fc, Formula 7, R p-Br--C.sub.6H.sub.4;
R.sub.1 R.sub.2=CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
[0139] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-butenol
(4f, 500 mg) and methylene blue (5 mg) in CH.sub.3CN (35 ml) and
CH.sub.2Cl.sub.2 (35 ml) was photooxygenated at -6.degree. C. for
3.5 h. Cyclohexanone (1 ml) and p-toluenesulfonic acid (60 mg) were
added and reaction mixture was left at r.t. for 18 h. The reaction
mixture was diluted with saturated NaHCO.sub.3 solution (5 ml) and
worked up as above and concentrated. Crude product was purified by
column chromatography to furnish 320 mg (47% yield, based on
allylic alcohol 4f, used) of trioxane 7fc, m.p. 118-120.degree.
C.
EXAMPLE 31
[0140] Trioxane 7fd, Formula 7, R=p-Br--C.sub.6H.sub.4,
R.sub.1R.sub.2==--CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub.2CH.sub.2CH.sub.-
3]--CH.sub.2--CH.sub.2--
[0141] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4yl)-2-butenol
(4f, 500 gm) and methylene blue (2 mg) in CH.sub.3CN (40 ml) and
CH.sub.2Cl.sub.2 (40 ml) was photooxygenated at -6.degree. C. for 3
h. 4-t-amyl cyclohexanone (1.5 ml) and p-toluenesulfonic acid (50
mg) were added and reaction mixture was left at r.t. for 17 h. The
reaction mixture was worked up and concentrated. Crude product was
purified by column chromatography to furnish 480 mg (60% yield,
based on allylic alcohol, 4f used) of trioxane 7fd m.p.
122-124.degree. C.
EXAMPLE 32
[0142] Trioxane 8f, Formula 8, R=p-Br--C.sub.6H.sub.4
[0143] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4yl)-2-butenol
(4f, 350 mg) and methylene blue (2 mg) in CH.sub.3CN (25 ml) and
CH.sub.2Cl.sub.2 (25 ml) was photooxygenated at -6.degree. C. for 3
h. Norcamphor (750 mg) and p-toluenesulfonic acid (50 mg) were
added and the reaction mixture was stirred at r.t. for 18 h. The
reaction mixture was worked up as above and concentrated. Crude
product was purified by column chromatography on silica gel to
furnish 300 mg (42.8% yield, based on allylic alcohol, 4f used) of
trioxane 8f, m.p. 122-124.degree. C.
EXAMPLE 33
[0144] Trioxane 9f, Formula 9, R=p-Br--C.sub.6H.sub.4
[0145] A solution of 3-(4'-bromo-[1,1'-biphenyl]-4yl)-2-butenol
(4f, 500 mg) and methylene blue (2 mg) in CH.sub.3CN (40 ml) and
CH.sub.2Cl.sub.2 (40 ml) was photoooxygenated at 5.degree. C. for 5
h. 2-Adamantanone (1 g) and p-toluenesulfonic acid (60 mg) were
added and reaction mixture was stirred for 30 minutes and then left
at r.t. for 16 h. Reaction mixture was worked as above and
concentrated. Crude product was purified by column chromatography
to furnish 490 mg (63.6% yield, based on allylic alcohol 4f, used)
of trioxane 9f mp 118.degree. C.
EXAMPLE 34
[0146] Ethyl 3-(4'-chloro-[1,1'-biphenyl]-4-yl)-but-2-enoate
(Compound 3g, Formula 3, R=p-Cl--C.sub.6H.sub.4)
[0147] To a refluxing mixture of 4-(4'-chlorophenyl)acetophenone
(8.46 g), I.sub.2 (5 mg) and Zn (2.55 g) in benzene (200 ml) was
added ethylbromoacetate (4.35 ml) dropwise during 30 minutes. The
mixture was refluxed for 2 h and then cooled to room temperature.
It was acidified with 10% HCl (75 ml) and benzene layer was
separated. Organic layer was washed with water, dried
(Na.sub.2SO.sub.4) and concentrated. Crude .beta.-hydroxyester
(compound 2g, formula 2, R=p-Cl--C.sub.6H.sub.4) was used as such
without purification for the preparation of ethyl
3-(4'-chloro-[1,1'-biphenyl]-4-yl)-but-2-enoate as follows:
[0148] To a solution of crude ethyl
3-hydroxy-3-(4'-chloro-[1,1'-biphenyl]- -4-yl)-butanoate (2g) in
benzene (200 ml) was added p-toluenesulfonic acid (3 gm) and was
refluxed for 3 h 30 minutes. The reaction mixture was cooled,
neutralized with NaHCO.sub.3 solution, diluted with water and
organic layer was extracted. Organic layer was washed with water,
dried (NaHCO.sub.3) and concentrated. Crude product was purified by
column chromatography on silica gel to furnish 5.27 g (47.=91%
yield) of ethyl 3-(4'-chloro-[1,1'-biphenyl]-4-yl)-but-2-enoate
(3g, formula 3, R=p-C.sub.1-C.sub.6H.sub.4) m.p. 91-94.degree.
C.
[0149] 3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-butenol (Compound 4g,
Formula 4, R=p-C.sub.1--C.sub.6H.sub.4)
[0150] To an ice cooled slurry of LiAlH.sub.4 (1.4 g) in dry ether
(200 ml) was added a solution of ethyl
3-(4'-chloro-[1,1'-biphenyl]-4-yl)-but-- 2-enoate (3g, 2.8 g) in
dry ether (50 ml) dropwise. The reaction mixture was stirred for 2
h at 0.degree. C. The reaction mixture was quenched with water. A
solution of 10% NaOH was added and the ether layer was decanted.
The precipitate was washed with ether and the combined ether
extract was concentrated. The crude product was chromatographed on
silica gel to give 1.8 g (75% yield) of
3-(4'-chloro-[1,1'-biphenyl]-4-yl)-buten- ol (4g, formula 4,
R=p-C.sub.1--C.sub.6H.sub.4) m.p. 130-132.degree. C.
[0151]
3-(4'-chloro-[1,1'-biphenyl]-4yl)-1-hydroxy-but-3-en-2-hydroperoxid-
e (Compound 5g, Formula 5, R=p-C.sub.1--C.sub.6H.sub.4)
[0152] A solution of 3-(4'-chloro-[1,1'-biphenyl]-4-yl)-2-butenol
(4g, 1 g) and methylene blue (40 mg) in acetonitrile (30 ml) was
irradiation with a 250-watt tungsten-halogen lamp at 10.degree. C.
while oxygen was passed through the reaction mixture for 5 h 30
minutes. Solid hydroperoxide separated out during the reaction was
collected by filtration to furnish 600 mg of hydroperoxide 5g. The
filtrate was chromatographed on silica gel to give 260 mg of
hydroperoxide 5g. The combined yield of hydroperoxide (compound 5g,
formula 5, R=p-C.sub.1--C.sub.6H.sub.4) was 860 mg (76.7%
yield).
[0153] 8-[(4'-chloro-[1,1'-biphenyl]-4yl)vinyl]-6,7,10-trioxaspiro
(4,5) Decane (Trioxane 7ga, Formula 7, R=p-C.sub.1--C.sub.6H.sub.4,
R.sub.1R.sub.2=--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
[0154] A solution of 3-(4'-chloro-[1,1'-biphenyl]4yl)-2-butenol
(4g, 500 gm) and methylene blue (40 mg) in CH.sub.3CN (30 ml) was
photooxygenated at 5.degree. C. for 5 h. Cyclopentanone (0.5 ml)
and hydrochloric acid (5 drops) were added and reaction mixture was
stirred at r.t. for 1.5 h and then left at r.t for 48 h. The
reaction mixture was concentrated. Crude product was purified by
column chromatography to furnish 230 mg (33.8% yield, based on
allylic alcohol, 4g used) of trioxane 7ga m.p. 105-107.degree.
C.
EXAMPLE 35
[0155] 3-[(4'-chloro-[1,1'-biphenyl]-4-yl)-vinyl]-1,2,5-trioxaspiro
(5,5) Undecane (Trioxane 7gb, Formula 7,
R=p-C.sub.1--C.sub.6H.sub.4;
R.sub.1R.sub.2=CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--)
[0156] A solution of 3-[(4'-chloro-[1,1'-biphenyl]-4-yl)-2-butenol
(4g, 500 mg) and methylene blue (40 mg) in CH.sub.3CN (30 ml) was
photooxygenated at 5.degree. C. for 5 h. Cyclohexanone (0.5 ml) and
hydrochloric acid (5 drops) were added and reaction mixture was
stirred at r.t. for 1.5 h and then left at r.t for 24 h. The
reaction mixture was concentrated. Crude product was purified by
column chromatography to furnish 360 mg (50% yield, based on
allylic alcohol 4g, used) of trioxane 7gb, m.p. 109-111.degree.
C.
EXAMPLE 36
[0157] Trioxane 8g, Formula 8, R=p-C.sub.1--C.sub.6H.sub.4
[0158] To a solution of
3-(4'-chloro-[1,1'-biphenyl]-4yl)-1-hydroxy-but-3--
en-2-hydroperoxide (5g, 500 mg) and norcamphor (500 mg) in
chloroform (100 ml) was added hydrochloric acid (5 drops) and the
reaction mixture was stirred at r.t. for 1 h and then left at r.t
for 18 h. The reaction mixture was worked up as above and
concentrated. Crude product was purified by column chromatography
on silica gel followed by crystallization to furnish 420 mg (64.6%
yield) of trioxane 8g, m.p. 122-124.degree. C.
EXAMPLE 37
[0159] Trioxane 9g, Formula 9, R=p-C.sub.1--C.sub.6H.sub.4
[0160] A solution of 3-(4'-chloro-[1,1'-biphenyl]-4yl)-2-butenol
(4g, 500 mg) and methylene blue (50 mg) in CH.sub.3CN (60 ml) was
photoooxygenated at 5.degree. C. for 5 h. 2-Adamantanone (1 g) and
hydrochloric acid (5 drops) were added and reaction mixture was
stirred at r.t. for 2 h and then left at r.t for 16 h. The reaction
mixture was worked up and concentrated. Crude product was purified
by column chromatography to furnish 560 mg (69.14% yield, based on
allylic alcohol 4g, used) of trioxane 9g, m.p. 112-115.degree.
C.
[0161] Following the Above Procedure the Following Trioxanes were
Prepared:
7 S.No. Trioxane m.p. % Yield 1. 8-[(4
-Cyclopentylphenyl)vinyl]-6,7,10- oil 52.7 trioxaspiro-[4,5]-decane
(trioxane 7aa, formula 7, R = cyclopentyl; R.sub.1 R.sub.2 =
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2) 2. Trioxane 7ab, formula 7, R =
cyclopentyl ; R.sub.1 98-100.degree. C. 60.2 R.sub.2 =
--CH.sub.2CH.sub.2CH(Ph)CH.sub.2CH.sub.2-- 3.
3-[(4'-cyclopentylphenyl)vinyl]-1,2,5- 57-58.degree. C. 50.6
trioxaspiro(5,5)undecane (7ac, formula 7, R = cyclopentyl, R.sub.1
R.sub.2 = --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 4.
3-[(4-cyclopentylphenyl)vinyl-1,2,5- Oil 29.1 trioxaspira
(5,6)dodecane (7ad, formula 7, R = cyclopentyl, R.sub.1R.sub.2 =
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2 CH.sub.2--) 5. Trioxane
7ae, formula 7, R = cyclopentyl, R.sub.1 95-97.degree. C. 47.8
R.sub.2 = CH.sub.2--CH.sub.2--CH(C(CH.sub.3).sub.2CH.sub.2CH-
.sub.3)--CH.sub.2CH.sub.2-- 6. Trioxane belonging to norcamphor
group(8a 91-93.degree. C. 28 R = cyclopentyl) 7. Trioxane belonging
to adamantane group (9a 74-76.degree. C. 49.4 R = cyclopentyl) 8.
3,3-dimethyl-6-[4'-cyclohexylphenyl]vinyl- 54-55.degree. C. 76.9
1,2,4-trioxane (trioxane 7ba, formula 7, R = cyclohexyl) 9.
3-Decyl-3-methyl-6-[(4'-cyclohexylpheny- l) oil 31.1
vinyl]-1,2,4-trioxane (trioxane 7bb, formula 7, R = cyclohexyl) 10
6-[(4-cyclohexylphenyl)vinyl]-3-phenyl-1,2,4- - 86-88.degree. C.
44.7 trioxane (trioxane 7bc, formula 7, R = cyclohexyl] 11
3-[(4'-Cyclohexylphenyl)vinyl]-1,2,5- 60-62.degree. C. 74.3
trioxaspiro(5,5)undecane (trioxane 7bd, formula 7, R = cyclohexyl,
R.sub.1R.sub.2 = --CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 12.
Trioxane 7be, formula 7, R = cyclohexyl, 107-109.degree. C. 63.3
R.sub.1R.sub.2 = --CH.sub.2--CH.sub.2--CH(Ph)CH.sub.2CH.sub.2-- 13.
3-ethyl-3-methyl-6-[4-cyclohexyl Oil 20 phenyl)vinyl]-1,2,4-triox-
ane (7bf, formula 7, R = cyclohexyl, R.sub.1, R.sub.2 = CH.sub.3,
--CH.sub.2CH.sub.3) 14. 3-Methyl-3-propyl-6-[4-cyclohexyl Oil 28.1
phenyl)vinyl]-1,2,4-trioxane (7bg, formula 7, R = cyclohexyl,
R.sub.1, R.sub.2 = CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3) 15.
8-[(4-cyclohexylphenyl)vinyl]-6,7,10- 43-45.degree. C. 39.4
trioxaspiro (4,5) decane (7bh, formula 7, R = cyclohexyl, R.sub.1
R.sub.2 = --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) 16.
Trioxane7bi, formula 7, R = cyclohexyl, R.sub.1 R.sub.2 =
90-92.degree. C. 50.5
CH.sub.2--CH.sub.2--CH(C(CH.sub.3).sub.2CH.sub.2CH.sub.3)-
--CH.sub.2CH.sub.2-- 17. Trioxane belonging to norcamphor group(8b
70-71.degree. C. 40.8 R = cyclohexyl) 18. Trioxane belonging to
adamantane group (9b 75-76.degree. C. 58.8 R = cyclohexyl) 19.
3-[(4-cycloheptylphenyl)vinyl]-1,2,5- 55-57.degree. C. 50
trioxaspiro-[5,5]-undecane (trioxane 7ca, formula 7, R =
cycloheptyl; R.sub.1 R.sub.2 =
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 20. Trioxane 7cb,
formula 7, R = cycloheptyl ; 58-60.degree. C. 45.9 R.sub.1R.sub.2 =
--CH.sub.2--CH.sub.2--CH(C(CH.sub.3).sub.2CH.sub.2CH.sub- .3--
CH.sub.2CH.sub.2- 21. 8-[4'-cycloheptylphenyl)vinyl]- -6,7,10- Oil
65 trioxaspiro(4,5)decane (7cc,formula 7, R = cycloheptyl, R.sub.1
R.sub.2 = CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- 22. Trioxane
7cd, formula 7, R = cycloheptyl, 92-95.degree. C. 44 R.sub.1R.sub.2
= CH.sub.2--CH.sub.2--CH(Ph)-CH.sub.2--CH.sub.2--) 23. Trioxane
belonging to norcamphor group(8c 65-68.degree. C. 38.6 R =
cycloheptyl) 24. Trioxane belonging to adamantane group (9c oil
50.6 R = cycloheptyl) 25. 3-ethyl-3-methyl-6-[(4'-cyclooctylphenyl)
oil 28.7 vinyl]-1,2,4-trioxane (compound 7da, formula 7, R =
cyclooctyl) 26. 3-[(4'-cyclooctylphenyl)vinyl]-1,2,5- 58-60.degree.
C. 47.8 trioxaspiro-(5,5)-undecane (trioxane 7db, formula 7, R =
cyclooctyl; R.sub.1 R.sub.2 = --CH.sub.2CH.sub.2CH.sub.2CH.sub.2-
CH.sub.2--) 27. 3-[(4'-cyclooctylphenyl)vinyl]-1,2,5- oil 28.3
trioxaspiro-(6,5)-dodecane (trioxane 7dc, formula 7, R =
cyclooctyl; R.sub.1 R.sub.2 = --CH.sub.2CH.sub.2CH.sub.2CH.sub.2-
CH.sub.2CH.sub.2--) 28. Trioxane 7dd, formula 7, R = cyclooctyl,
R.sub.1R.sub.2 = 95-97.degree. C. 39.5 CH.sub.2--CH.sub.2--CH(Ph-
)-CH.sub.2--CH.sub.2--) 29. 8-[(4'-cyclooctylphenyl)vinyl]-6,7,10-
Oil 45.5 trioxaspiro(4,5)undecane (7de, formula 7, R = cycloheptyl,
R.sub.1R.sub.2 = CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--) 30.
Trioxane 7df, formula 7, R = cyclooctyl, R.sub.1R.sub.2 =
89-91.degree. C. 51.7 CH.sub.2--CH.sub.2--CH(C(CH.sub.3).sub.2CH.-
sub.2CH.sub.3)--CH.sub.2CH.sub.2-- 31. Trioxane belonging to
norcamphor group(8d oil 47.5 R = cyclooctyl) 32. Trioxane belonging
to adamantane group (9d oil 44.4 R = cyclooctyl) 33.
6-[([1,1'-biphenyl]-4yl)vinyl]-3-phenyl-1,2,4- 110-112.degree. C.
70 trioxane (7ea, formula 7, R = Ph, R.sub.1,R.sub.2 = H, Ph). 34.
8-[([1,1'-biphenyl]-4yl)vinyl]-6,7,10- 102-104.degree. C. 45.1
trioxaspiro (4,5) decane (7eb, formula 7, R = Ph, R.sub.1R.sub.2 =
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 35.
3-[([1,1'-biphenyl]-4yl)vinyl]-1,2,5-trioxaspiro 96-98.degree. C.
46.1 (5,5) undecane (7ec, formula 7, R = Ph, R.sub.1R.sub.2 =
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 36.
3-Decyl-3-Methyl-6-[([1,1'-biphenyl]-4-yl)- 86-90.degree. C. 27
vinyl]-1,2,4-trioxane (7ed, formula 7, R = Ph; R.sub.1, R.sub.2 =
CH.sub.3, --CH.sub.2(CH.sub.2).sub.8CH.sub.3) 37.
3,3-Dimethyl-6-[([1,1'-biphenyl]-4yl)vinyl]- 90-92.degree. C. 37.2
1,2,4-trioxane (7ee, formula 7, R = Ph, R.sub.1, R.sub.2 =
CH.sub.3,CH.sub.3) 38. Trioxane 7ef, formula 7, R = Ph, R.sub.1
R.sub.2 = 150-154.degree. C. 81 --CH.sub.2CH.sub.2CH(Ph)CH.sub.2C-
H.sub.2-- 39. Trioxane 7eg, formula 7, R = Ph, R.sub.1R.sub.2 =
CH.sub.2-- 94-98.degree. C. 85.5 CH.sub.2--CH(C(CH.sub.3).sub.2C-
H.sub.2CH.sub.3)--CH.sub.2CH.sub.2--) 40. 3[([1,1'-biphenyl]-4yl)v-
inyl]-1,2,5- 90-92.degree. C. 24.6 trioxaspiro(5,6)dodecane (7eh,
formula 7, R = Ph, R.sub.1 R.sub.2 = CH.sub.2CH.sub.2CH.sub.2CH.-
sub.2CH.sub.2 CH.sub.2--) 41. Trioxane belonging to norcamphor
group(8e 86-90.degree. C. 45.1 R = Ph) 42. Trioxane belonging to
adamantane group (9e 94-96.degree. C. 71.04 R = Ph) 43.
3,3-Dimethyl-6-[(4'-bromo-[1,1'-biphenyl]-4- 92-95.degree. C. 69.7
yl)- vinyl]-1,2,4-trioxane (7fa, formula 7, R =
p-Br--C.sub.6H.sub.4; R.sub.1, R.sub.2 = CH.sub.3, CH.sub.3) 44.
3-Ethyl-3-methly-6-[(4'-bromo-[1,1'-biphenyl]- 82-85.degree. C.
37.5 4-yl)-vinyl]-1,2,4-trioxane ( 7fb, formula 7, R =
p-Br--C.sub.6H.sub.4; R.sub.1, R.sub.2 = CH.sub.3,
CH.sub.2CH.sub.3) 45.
3-[(4'-bromo-[1,1'-biphenyl]-4-yl)-vinyl]-1,2,5- 118-120.degree. C.
47 trioxaspiro (5,5) undecane (7fc , formula 7, R =
p-Br--C.sub.6H.sub.4; R.sub.1 R.sub.2 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.2C- H.sub.2--) 46. Trioxane
7fd,formula 7, R = p-Br--C.sub.6H.sub.4, R.sub.1 R.sub.2 ==
122-124.degree. C. 60 --CH.sub.2CH.sub.2--CH[C-
(CH.sub.3).sub.2CH.sub.2CH.sub.3]--CH.sub.2-CH.sub.2- 47.
8-[(4'-bromo-[1,1'-biphenyl]-4yl)vinyl]-6,7,10- 104-106.degree. C.
66.6 trioxaspiro (4,5) decane (7fe, formuma 7, R =
p-Br--C.sub.6H.sub.4, R.sub.1 R.sub.2 =
--CH.sub.2--CH.sub.2--CH.sub.2--C- H.sub.2--) 48. Trioxane 7ff,
formula 7, R = p-Br--C.sub.6H.sub.4, R.sub.1 R.sub.2 =
104-106.degree. C. 66.6 CH.sub.2--CH.sub.2--CH(-
Ph)-CH.sub.2--CH.sub.2-- 49. Trioxane belonging to norcamphor
group(8f 122-124.degree. C. 42.8 R = p-Br--C.sub.6H.sub.4) 50.
Trioxane belonging to adamantane group (9f 118.degree. C. 63.6 R =
p-Br--C.sub.6H.sub.4) 51. 8-[(4'-chloro-[1,1'-biphenyl]-4yl-
)vinyl]-6,7,10- 105-107.degree. C. 33.8 trioxaspiro (4,5) decane
(7ga, formula 7, R = p-Cl--C.sub.6H.sub.4, R.sub.1R.sub.2 =
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 52 3-[(4'-chloro-[1,1'-biph-
enyl]-4-yl)-vinyl]-1,2,5- 109-111.degree. C. 50 trioxaspiro (5,5)
undecane (7gb , formula 7, R = p-Cl--C.sub.6H.sub.4; R.sub.1
R.sub.2 = CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) 53. Trioxane
7gc, formula 7, R = p-Cl--C.sub.6H.sub.4, R.sub.1 R.sub.2 =
145-148.degree. C. 24.4 CH.sub.2CH.sub.2CH(Ph)CH.sub.2CH.sub.2--)
54. Trioxane 7gd, formula 7, p-Cl--C.sub.6H.sub.4, R.sub.1R.sub.2 =
115-148.degree. C. 35.3 CH.sub.2--CH.sub.2--CH[C(CH.sub.3).sub.-
2CH.sub.2CH.sub.3]--CH.sub.2CH.sub.2-- 55. 3-Ethyl-3-methyl-6-[(4'-
-chloro-[1,1'-biphenyl]- 70-72.degree. C. 67.7
4yl)vinyl]-1,2,4-trioxane (7ge, formula 7, R =
p-Cl--C.sub.6H.sub.4, R.sub.1, R.sub.2 = CH.sub.3,CH.sub.2CH.sub.3)
56. Trioxane belonging to norcamphor group(8g, 122-124.degree. C.
64.6 R = p-Cl--C.sub.6H.sub.4) 57. Trioxane belonging to adamantane
group (9g, 112-115.degree. C. 69.14 R = p-Cl--C.sub.6H.sub.4)
[0162] Antimalarial Activity
[0163] The antimalarial activity of the test compounds was
evaluated in rodent using multidrug resistant strain of Plasmodium
yoelii Nigeriensis in swiss mice.
[0164] General Procedure: Random bred swiss mice of either sex
(20.+-.2 gm) were inoculated intraperitoneally with
1.times.10.sup.5 P. yoelli (MDR) parasites on day zero. The
treatments with test compounds were administered to group of 5 mice
each at different dose levels ranging between 24-96 mg/kg/day. The
treatment was administered via intramuscular route for 4
consecutive days (day 0-3).
[0165] Blood smears from experimental mice were observed on day 4
and 7, day 10 and thereafter at regular intervals till day 28 or
death of the animal. The parasitaemia level on day 4 was compared
with the vehicle control group and the present suppression of
parasitaemia in treated groups was calculated.
[0166] For determining the curative dose of a compound the treated
mice were observed till day 28. The dose at which no parasitaemia
develop during the observation period has been reported as the
curative dose. The anti-malarial data is summarized in table 7.
8TABLE 7 ANTIMALARIAL ACTIVITY OF TRIOXANES AGAINST P. yoelii IN
MICE % Compd. Dose No. Of Suppression No. Route Mg/kg Animals on
Day 4 Cured/treated 7aa i.m. 96 5 100 0/5 oral 96 5 100 5/5 7ab
i.m. 96 5 77.56 0/5 oral 96 5 100 0/5 7ac i.m. 96 5 84.94 0/5 oral
96 5 100 5/5 7ad i.m. 96 5 48 0/5 oral 96 5 88.68 0/5 7ae i.m. 96 5
43.58 0/5 oral 96 5 100 0/5 7ba i.m. 96 5 71.26 0/5 oral 96 5 100
0/5 7bc i.m. 96 5 41.98 0/5 oral 96 5 95.64 0/5 7bd i.m. 96 5 71.73
0/5 oral 96 5 100 5/5 7be i.m. 96 5 91.6 0/5 oral 48 5 100 5/5 7bf
i.m. 96 5 71.26 0/5 oral 96 5 100 0/5 7bh i.m. 96 4 100 1/4 oral 96
4 100 4/4 7bi i.m. 96 5 53.01 0/5 oral 96 5 100 5/5 7ca i.m. 96 5
62.18 0/5 oral 96 5 100 1/5 7cb i.m. 96 5 86.31 0/5 oral 96 5 100
5/5 7cd i.m. 96 5 58.17 0/5 oral 96 5 100 2/5 7db i.m. 96 5 9.5 0/5
oral 96 5 100 5/5 7dd i.m. 96 5 73.81 0/5 oral 96 5 100 4/5 7de
i.m. 96 5 57.4 0/5 oral 96 5 100 3/5 7df i.m. 96 5 0 0/5 oral 96 5
100 3/5 7eb i.m. 96 6 100 6/6 oral 96 5 100 0/5 7ec i.m. 96 4 100
0/4 oral 96 4 100 4/4 7ee i.m. 96 5 60.9 0/5 oral 96 5 96.8 0/5 7ef
i.m. 96 5 42.7 0/5 oral 96 5 100 2/5 7eg i.m. 96 5 87.6 0/5 oral 96
5 100 3/5 7eh i.m. 96 5 92 0/5 oral 96 5 100 4/5 7fa i.m. 96 5 83.7
0/5 oral 96 5 died -- 7fb i.m. 96 4 51.41 0/5 oral 96 4 100 0/5 7fc
i.m. 96 5 46.4 1/5 oral 96 5 100 5/5 7fd i.m. 48 5 51.09 0/5 oral
96 5 88.39 0/5 7fe i.m. 96 4 89.4 0/5 oral 96 4 100 3/5 7ff i.m. 96
4 46.1 0/5 oral 96 4 100 2/5 8a i.m. 96 5 81.23 0/5 oral 96 5 100
5/5 8b i.m. 96 5 100 3/5 oral 48 6 100 6/6 8c i.m. 96 5 43.55 0/5
oral 96 5 100 3/5 8e i.m. 96 4 100 1/4 oral 96 4 100 4/4 8f i.m. 96
5 100 0/5 oral 96 5 100 5/5 9a i.m. 96 5 81.23 0/5 oral 96 5 100
5/5 9b i.m. 96 5 82.16 0/5 oral 96 5 100 5/5 9c i.m. 96 5 74.57 0/5
oral 96 5 100 5/5 9d i.m. 96 5 60.12 0/5 oral 96 5 100 5/5 9e i.m.
96 6 100 0/6 oral 96 6 100 6/6 9f i.m. 96 5 92.4 2/5 oral 48 5 100
5/5 9g i.m. 96 5 100 -- oral 96 5 100 3/5
* * * * *